Citations

AbstractBackgroundPrucalopride is a high‐affinity 5‐HT4 receptor agonist for the treatment of chronic constipation. The aims of this study were to investigate the relationship between health‐related quality of life (HRQoL) and symptoms of constipation, and to assess the response of HRQoL to treatment using integrated data from three phase III trials of prucalopride.MethodsThis was an integrated analysis of data from three pivotal multicenter, double‐blind, randomized, placebo‐controlled, parallel‐group trials (ClinicalTrials.gov Identifiers: NCT00488137, NCT00483886 and NCT00485940). Relationships were investigated between Patient Assessment of Constipation Quality of Life (PAC‐QOL) scores, Patient Assessment of Constipation Symptoms (PAC‐SYM) scores, bowel movement frequency (assessed using daily diaries), and treatment.Key ResultsPatients treated with prucalopride 2 mg (n = 659) and placebo (n = 661) were included in the analysis. An improvement in PAC‐SYM scores correlated well with an improvement in PAC‐QOL overall score (r = 0.711) and satisfaction subscale score (r = 0.589). After 12 weeks, PAC‐QOL overall score and satisfaction subscale score significantly (p < 0.001) improved by ≥1 point (clinically relevant) in 36.5% and 44.1% of patients treated with prucalopride, compared with 18.5% and 22.4% with placebo respectively. Moreover, 39.0% of patients with an improvement in satisfaction of ≥1 point achieved ≥3 spontaneous complete bowel movements/week, compared with 7.4% of those with no improvement in satisfaction (<1 point).Conclusions & InferencesImprovements in PAC‐QOL overall score and satisfaction score were associated with improvements in symptoms of chronic constipation. Compared with placebo, treatment with prucalopride significantly improved HRQoL.

AbstractBackgroundSynthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM‐131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)‐1a (also called the ghrelin) receptor with approximately sixfold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin.PurposeIn this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a prespecified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders.

AbstractBackgroundIntensive treatment options are lacking for patients with severe skin disease recalcitrant to outpatient therapy. The availability of inpatient dermatology care has almost disappeared in many parts of the United States. One possible solution for this is a day treatment center for patients with severe dermatologic disease recalcitrant to outpatient therapy.MethodsDescriptive study based on retrospective medical record review of all patients attending the day hospital for treatment in 2010. We collected data on patient demographics, distribution of admission diagnosis, treatments used, and length of stay.ResultsA total of 211 patients had 235 admissions. Mean age was 57.7 years (range 3.8–92.1 years). The most common indications for admission were dermatitis (139 admissions [59.2%]), psoriasis (58 [24.7%]), and mycosis fungoides (eight [3.4%]). The main treatment interventions were wet dressings (195 admissions [83.0%]) and Goeckerman treatment (38 [16.2%]). The median number of days of treatment was three (interquartile range, 2–5 days) for wet dressings and 22 days (interquartile range, 21–24 days) for Goeckerman therapy.ConclusionsThe dermatology day treatment center provided intensive skin‐directed therapy and filled a critical practice gap in the management of our patients with severe widespread skin diseases recalcitrant to outpatient therapy. We propose that the dermatology day treatment center is a valuable model that could be considered by both private practitioners and academic centers in the United States as an important adjunct to fill the gap in availability of intensive topical treatments for patients with severe skin disease.

AbstractBackgroundDermatology consultations are frequently requested by inpatient hospital services. As inpatient dermatology services in the USA decline, dermatology hospital consultations are becoming increasingly important.ObjectivesWe aim to describe the spectrum of skin diseases encountered and the health care subspecialties requesting dermatology hospital consultations.MethodsWe performed a retrospective chart review of adult patient (age: ≥18 years) dermatology hospital consultations from January 1 to December 31, 2010. We examined patient demographic characteristics, consultation requesting services, and consultation diagnoses.ResultsAmong dermatology services, 614 patients had 674 separate inpatient dermatology consultations during 2010. Of these patients, 55.9% were male (mean age: 59 years). In total, 205 consultations (30.4%) were requested by the internal medicine subspecialty, 137 (20.3%) by the hematology and oncology subspecialty, and 93 (13.8%) by the surgical subspecialty. The most common conditions seen by the hospital dermatology consulting service were skin infections (n = 125, 18.5%), dermatitis (n = 120, 17.8%), drug eruptions (n = 87, 12.9%), chronic wounds and ulcers (n = 55, 8.1%), cutaneous neoplasms (n = 39, 5.8%), graft‐versus‐host disease (n = 37, 5.5%), ecchymosis, purpura simplex or petechia (n = 26, 3.8%), intertrigo (n = 21, 3.1%), and urticaria (n = 20, 3.0%).ConclusionsThe majority of consultations conducted by the dermatology hospital consulting service were for the management of common skin diseases, such as cutaneous infections, dermatitis, and drug eruptions. Most consultations were requested by the departments of internal medicine, hematology and oncology, and surgical services.

BackgroundOptimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS‐C) are uncertain.ObjectiveThe objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS‐C symptoms.MethodsUsing pooled 12‐week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed.ResultsCorrelations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48–0.54, 0.32–0.39, and 0.61–0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS‐C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%–76% and 71%–82% of weeks with agreement, respectively).ConclusionsAR bridges IBS‐C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.

Objective IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. Design We conducted a GWA study (GWAS) of IBS in a general population sample of 11 326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. Results One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10 −6 in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. Conclusions Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.

AbstractBackgroundA valid biomarker is ‘an indicator of normal biologic or pathogenic processes, or pharmacological responses to a therapeutic intervention’. There is no validated biomarker for irritable bowel syndrome (IBS). The aim of the study was to assess ability of three quantitative traits to identify treatable processes to discriminate between IBS‐diarrhea (IBS‐D) patients, IBS‐constipation (IBS‐C) patients and healthy volunteers (HV).MethodsIn 30 HV, 30 IBS‐C patients and 64 IBS‐D patients, we characterized bowel symptoms and quantitated pathophysiological mechanisms: bile acid (BA) synthesis (serum C4 and FGF19), fecal BA and fat, colonic transit (CT), and intestinal permeability (IP). We used multiple logistic regression and receiver‐operating characteristic (ROCAUC) to appraise three factors (fecal BA, CT, and IP) individually and in combination to identify discriminant targets for treatment in IBS.Key ResultsThere were significant associations between the three subgroups and symptoms reflecting bowel function and the quantitative traits. There were significant associations between fecal BA and CT at 48 h (r = 0.43; p < 0.001) and between fecal BA and IP (r = 0.23; p = 0.015). Individually, fecal BA and CT48 (but not IP) were significant independent predictors for distinguishing HV from IBS. In combination, they discriminated HV from IBS‐D patients (ROCAUC 0.70), HV from IBS‐C patients (ROCAUC 0.73), and IBS‐C patients from IBS‐D patients (ROCAUC 0.86). Colonic transit and fecal BA excretion together discriminate between healthy volunteers and IBS‐C patients or IBS‐D patients, or between the IBS subgroups with 75–90% specificity at 60% sensitivity.Conclusions & InferencesColonic transit and fecal BA individually and together constitute useful biomarkers to identify treatable mechanisms in IBS and to differentiate subgroups of IBS.

AbstractBackgroundThe utility of diagnostic imaging in paraneoplastic autoimmune multiorgan syndrome (PAMS) is unknown.MethodsWe examined the role of diagnostic imaging in patients with PAMS evaluated at our tertiary referral center (at Mayo Clinic, Rochester, MN, USA) and in the English literature between January 1, 1996, and August 31, 2012.ResultsWe included 17 patients from our institution and 208 patients from the literature review. Of these 225 patients, 113 (50.2%) were not known to have a malignancy diagnosis at the time of PAMS diagnosis. Of the 123 patients from our institution and from the literature reported to undergo imaging studies, conventional computed tomography (CT) was the predominant imaging modality (n = 110; 89.4%); 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET)/CT was also used, albeit infrequently (n = 12; 9.8%). When CT was included in imaging to identify or confirm the presence of a malignancy, imaging was successful in all patients who ultimately were diagnosed with an associated malignancy. At our institution, a relatively high percentage (n = 7; 41%) of patients had 18F‐FDG PET/CT, which not only identified all tumors found on CT but also facilitated staging of lymphoma and guided biopsy procedures.ConclusionDiagnostic imaging is frequently utilized in PAMS with unknown malignancy. Both conventional CT and 18F‐FDG PET/CT are likely to detect the typical underlying neoplasms. Relative to conventional CT, 18F‐FDG PET/CT may provide additional useful information regarding prognosis for the likely underlying malignancies, although there is a paucity of reports describing the use of this modality for this purpose.